ReviewAnti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection
Graphical abstract
Introduction
Inflammation is a vital host response to the loss of cellular and tissue homeostasis with many important roles, such as host defense; tissue remodeling and repair; and regulation of metabolism. Upon infection or tissue damage, a cascade of signals leads to the recruitment of inflammatory cells, particularly phagocytes such as neutrophils and macrophages. Immune activation in the central nervous system (CNS) is a classical feature of stroke, neurodegenerative diseases, spinal cord injury, multiple sclerosis, and brain injury. In the CNS, the innate immune system is represented by a type of macrophage, known collectively as microglia, originally described as a member of the reticuloendothelial system by Ramón y Cajal and Pío del Río Hortega in the 1920s. While microglia-driven neuroinflammation has a beneficial effect on scavenging cell debris, tissue healing, and repair; it is also been widely accepted that a chronic activation of this cell type leads to noxious effects on neurons and, thus, contributes to the pathophysiology of neurodegenerative diseases.
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels comprising a family of hetero- or homopentameric structures, which have an important role in multiple biological processes (memory, learning, locomotion, attention, and anxiety). Signaling through α7 nAChR subtype is involved in a variety of biological functions such as neuroprotection, synaptic plasticity and neuronal survival; and is considered a prominent therapeutic target in several diseases. In recent years, nAChRs have been shown to regulate inflammation, in particular via the α7 nAChR activation in macrophages [1], which regulates the “cholinergic anti-inflammatory pathway” [1], [2]. The transcripts for the nAChR subunits α7, α3, α5, as well as β4 have been detected in inflammatory cell types, including macrophages and microglia [3], [4]. The “cholinergic anti-inflammatory pathway” and its role in immunity and inflammation have attracted considerable interest due to their involvement in various human pathologies, including sepsis, diabetes, neurodegenerative diseases, osteoarthritis, and inflammatory bowel disease.
Here, we review our understanding of the cellular mechanisms by which α7 nAChR could modulate neuroinflammation and discuss the importance of this pathway in the resolution of neuroinflammation by microglia as well as its role in neuroprotection.
Section snippets
nACh receptors
nAChRs, which are the prototype of the cys-loop family of ligand-gated ion channels that also include GABAA, GABAC, glycine, 5HT3 receptors and 5-HT-gated chloride channels [5], [6]. The nAChRs are widely distributed throughout the central and peripheral nervous system (CNS and PNS), as well as the immune system and other peripheral tissues [7], [8]. Each receptor comprises five subunits assembled around an axis of pseudo-symmetry formed by the ionic pore. In the mammalian brain, 12 genes
α7 nAChRs and neuroprotection
Several clinical trials have evaluated the role and contribution of anti-inflammatory molecules in neurodegenerative diseases, potentially linking anti-inflammatory events with neuroprotective mechanisms [31]. From a pathological point of view, alterations in α7 nAChR have been related to different diseases, such as, neurodegenerative diseases, brain ischemia, schizophrenia and pain, for instance [12], [32], [33], [34]. Moreover, nAChR dysfunction is involved in the pathophysiology of diverse
α7 nAChRs in non-neuronal cells
Although the function of nAChR in neuronal populations is well characterized, their expression and relevance in glial cells has not been yet thoroughly explored. Most neurodegenerative diseases are associated to chronic inflammation, where the activation of the microglia, the brain resident immune cells, plays a pivotal role. In the PNS, α7 nAChRs expressed in blood-bone macrophages have been shown to drive the so-called “cholinergic anti-inflammatory pathway” that regulates systemic
The “cholinergic anti-inflammatory pathway”
The “cholinergic anti-inflammatory pathway” has an important role in immune responses and inflammatory cascades, which is mainly mediated by α7 nAChR in PNS. Cytokines play a central role in the immune response. The cytokine response to infection or injury is a well-orchestrated system that is successful in eradicating invading pathogens and in restoring tissue homeostasis. Pro- (e.g. TNF-α, IL6, IL1β, HMGB-1, IL12, IL18,…) and anti-inflammatory cytokines (IL10, IL4, TGF-β) are complementary
Jak2/STAT3 pathway
Jak/STAT signaling pathway is evolutionary conserved and mainly involved in cellular responses to different cytokines and growth factors. It comprises different proteins that were cloned in the 1990s, the Janus kinase (Jak), which involves four different tyrosine kinases: Jak1, Jak2, Jak3 and Tyk2 and the signal transducer and activators of transcription (STAT), including 7 transcription factors: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 [123]. The regulation of the pathway is highly
α7 nAChR/Nrf2/HO-1
Cells have developed several defence systems to combat oxidative damage generated by oxidative stress or electrophilic xenobiotics. The main antioxidant defence is the antioxidant pathway regulated by the transcription factor nuclear factor [erythroid-derived 2]-like 2 (Nrf2) [129]. Nrf2 is the major regulator of phase II and some phase III genes [130]. Under oxidative stress or xenobiotics conditions, Nrf2 translocates into the nucleus where it binds to specific DNA sites termed antioxidant
Microglial α7 nAChR/HO-1 pathway as an anti-inflammatory therapeutic target
Under normal/surveillance mode, microglia exhibit small cell bodies and thin processes that extend and branch several times. As part of microglia role in synapses maintenance, processes constantly inspect their surrounding environment for cellular debris or pathogens [150], [151]. When potentially dangerous signals are detected in the proximity, microglia polarization is triggered resulting in a pro-inflammatory phenotype phase of the cell known as M1 phase. Upon M1 activation microglia undergo
Conclusion
Here, we have reviewed the anti-inflammatory pathway promoted by α7 nAChR activation. This mechanism implies recruitment and activation of Jak2/STAT3 pathway, which on the one hand inhibits NF-κB nuclear translocation, and on the other hand, activates the master regulator of oxidative stress Nrf2/HO-1. Recently, we have demonstrated that activation of this pathway, specifically in microglial cells, may play a critical role in neuroprotection and anti-inflammatory processes [63]. We have
Acknowledgements
This work was supported by a grant from IS Carlos III, Programa Miguel Servet (CP14/00008) and IS Carlos III research contract under Miguel Servet Program to JE. MGL has a grant from Spanish Ministry of Economy and Competence Ref 2012-23332. RL has a grant from IS Carlos III, Programa Miguel Servet (CP11/00165) and FIS project (grant PI14/00372) and European Commission, Marie Curie Actions FP7 (FP7-People-2012-CIG-322156). We also thank the continuous support of Fundación Teófilo Hernando.
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